Kádár Kristóf

Deparment of Oralbiology

2016

Disorders of Ca/phosphate

homeostatsis:

Hyper- and hypocalcemias and the

osteoporosis

Calcium and Phosphate – Why is it

important?

• Phosphate is component of DNA, RNA, ATP,

phospholipids, and pH buffers – ~750 g in adult skeleton

– plasma concentration is 0.81-1.45 mmol/L

– 2 plasma forms: HPO42- and H2PO4

-

• Calcium needed in neurons, muscle

contraction,blood clotting and exocytosis – ~1100 g (28.6 mol) in adult skeleton

– plasma concentration is ~ 2.5 mmol/L

– In blood, 50% of Ca2+ binds to albumin

– Plasma ionized (free) Ca2+ level: 1.1-1.4 mmol/L.

– ionized (free) Ca2+biological effect (regulation signal)

Calcium and Phosphate – Why is it

important FOR A DENTIST?

• Complex and robust regulation exist to maintain ion

levels in the physiological range

• Main components of the mineralized tissue

• Chronic imbalances of phosphate/calcium regulation

results in the altered composition and mechanical

properites of the hard tissues!

Ion Imbalances • Changes in phosphate levels little effect

– chronic changes in phosphate levels→ changes in serum calcitriol,

PTH, FGF23,

– Ca2+

• Changes in calcium can be serious even life threatening

– hypocalcemia is deficiency of blood calcium (causes excitability of

nervous system if too low)

• Patomechanism: with less calcium, sodium channels open more easily,

sodium enters cell and excites neuron

• muscle spasms, tremors or tetany ~ 1.5 mmol/L

• laryngospasm and suffocation ~ 1.0 mmol/L

– hypercalcemia is excess of blood calcium

• Patomechanism: binding to cell surface makes sodium channels less likely

to open, depressing nervous system

• muscle weakness and sluggish reflexes, cardiac arrest ~ 3.0 mmol/L •

• Calcium/phosphate homeostasis depends on calcitriol,calcitonin,

PTH and FGF23 regulation

Hormonal control of calcium balance

7-Dehydrocholesterol

vitamin D3

UV light (skin)

25(OH)D3

liver

kidney

Prostate, breast,

colon, ß-cells etc.

autocrine effects: endocrine effects:

PTH

FGF23

+

+

+

+

-

-

+

1,24,25(OH)D3

inactive!

1,25(OH)D3 1,25(OH)D3 +

Calcitriol (activated vitamin D)

• Acts through the regulation of gene

expression – VDR receptor

• Calcitriol behaves as a hormone that raises

blood calcium concentration

– Increases intestinal absorption (calbindin, TRPV6)

and absorption from the skeleton

– increases stem cell differentiation into osteoclasts

– promotes urinary reabsorption of calcium ions

• Abnormal softness (rickets) in children and

(osteomalacia) in adults without vitamin D

Parathyroid Hormone

• Glands on posterior surface of thyroid

• Se [Ca2+]↓ CaSR PTH↑

• Main endocrine eunction raise calcium blood level

(Classical targets: osteblast, osteoclast, chondrocyte, renal tubular cells)

– causes osteoblasts to release osteoclast-

stimulating factor (RANKL) increasing osteoclast population

– promotes calcium resorption by the kidneys

– promotes calcitriol synthesis in the kidneys (activates 1(OH)-ase)

– inhibits phospahte reabsorption in the kidneys (inhibits SLC34A1,

SLC34A3)

– inhibits collagen synthesis and bone deposition by osteoblasts

• Non-classical target cells:

– smooth muscle (relaxation → hypotensive effect)

– cardiomyocytes (hypertrophy – eg. LVH in dialysed patients)

– sinus node (positive chronotropic effect)

FGF-23

• Fibroblast growth factor-23

• Produced mainly by bone and connective tissue

• Effects

– In the kidney

• inhibits tubular P reuptake – phosphaturia

• inhibits 1α-hydroxilase activity

– Induces 24-hydroxilase activity (calcitriol ↓) – indirectly decreases P

absorption

• Other effects

– Parathyroids:

• directly inhibits PTH secretion

– Cardiac:

• directly induces cardiac hypertrophy

• FGF23 mRNA expression is stimulated by:

– calcitriol

– hyperphosphataemia (indirect effect)

The regulation of calcium and phosphate homeostasis

by PTH, vitamin D and FGF23

DiGirolamo, D. J. et al. (2012) The skeleton as an endocrine organ Nat. Rev. Rheumatol. doi:10.1028/nrrheum.2012.157

Calcitonin

• Secreted (C cells of thyroid gland) when calcium concentration rises too high

• Functions

– reduces osteoclast activity as much as 70%

– increases the number and activity of osteoblasts

• Important in children, little effect in adults

– osteoclasts more active in children

– deficiency does not cause disease in adults

• Reduces bone loss in osteoporosis

Other hormones and local factors • Hormones

– insulin

– growth hormone (GH)

– glucocorticoids

– testosterone, oestrogen

– thyroid hormones

• Factors presumedly produced by the osteoblasts:

– IGF I

– FGF

– PDGF

– TGFb

• Factors produced by chondrocytes

– IGF I

– bFGF

– TGFb

• Factors produced by blood cells

– IL-1, IL-6

– Colony stimulating factors

– TNF

Main controlling mechanisms of calcium

homeostasis

Calcium balance

Causes of hypocalcemia

Hypoparathyroidism

Etiology

• Surgical

Hypoparathyroidism

• Idiopathic

Hypoparathyroidism

multi endocrine

deficiencyautoimmune-

candidiasis (MEDAC)

• Functional

Hypoparathyroidism

(low magnesium

intake, malabsorption)

Clinical features of hypoparathyroidism

• Neuromusclar manifestation

– Paresthesias (numbness, tingling)

– Hyperventilation

– Adrenergic symptoms (increased epinephrine)

– Signs of latent tetany

• Chvostek`s sign

• Trousseau`s sign

• Other clinical manifestation

– Posterior lenticular cataract

– Cardiac manifestation

– Dental manifestation

– Malabsorption syndrome

Clinical symptomes of hypocalcemic states

Etiologies of hypercalcemia

Increased GI Absorption

• Milk-alkali syndrome

• Elevated calcitriol

– Vitamin D excess: Excessive dietary intake, granulomatous disease

– Elevated PTH

– Hypophosphatemia

Increased loss from bone

• Increased net bone resorption

– Elevated PTH: Hyperparathyroidism (ie. primary hyperparathyroidism)

• Malignancy

– Osteolytic metastases, PTHrP secreting tumor, multiple myeloma

Increased bone turnover

– Paget’s disease, hyperthyroidism

Decreased bone mineralization

• Elevated PTH, aluminum toxicity

• Decreased urinary excretion

• Thiazide diuretics, elevated calcitriol, elevated PTH

Consequences of hypercalcemia

• Gastrointestinal – obstipatio, nausea, vomitting; ileus, abdominal pain

– ulcus pepticum, pancreatitis, anorexia

– polydipsia

• Renal – hypercalciuria, polyuria (Na and K loss), nycturia, albuminuria

– nephrolithiasis, nephrocalcinosis, azotaemia, renal insufficiency

• Neural – emotional instability, delirium, psychosis

– neuromuscular disorders, muscle weakness

• Circulation – hypertension, short QT, impulse formation and conduction

problems

Hyperparathyroidism (PTH↑)

• Primary hyperparathyroidism

– Parathyroid adenoma

– PTH producing tumor (MEN)

– Lab param.: se Ca ↑, se P ↓

• Secondary hyperparathyroidism

– Reactive PTH overproduction (cause: hypocalcaemia)

– eg. kidney insufficiency

– Lab param.: se Ca ↑, se P ↑

• Tertiary hyperparathyroidism

– After a long period of secondary hyperparathyrosidism in patients with kidney

insufficiency

– autonomous PTH hypersecretion, no response to drugs

– Therapy: surgical removal (3 + half gland)

– Lab param.: se Ca ↑, se P ↑

Primary hyperparathyroidism

Increased resorption of bone

surfaces Increased number of

osteoclasts, osteocytic osteolysis

Consequences of hypercalcemia

• Gastrointestinal – obstipatio, nausea, vomitting; ileus, abdominal pain

– ulcus pepticum, pancreatitis, anorexia

– polydipsia

• Renal – hypercalciuria, polyuria (Na and K loss), nycturia, albuminuria

– nephrolithiasis, nephrocalcinosis, azotaemia, renal insufficiency

• Neural – emotional instability, delirium, psychosis

– neuromuscular disorders, muscle weakness

• Circulation – hypertension, short QT, impulse formation and conduction

problems

Dental signs and symptoms

• Increased calcium levels in the saliva

• Increased calculus formation

• Widening of the periodontal space

• Absence of lamina dura

• Cystic lesions in the jawbone; filled with granulomatous tissue - epulis

Familial hypocalciuric hypercalcemia

(FHH)

• Genetic, autosomal dominant

• Mimics primary hyperparathyroidism

• PTH slightly high, however inappropriate for level of calcium

• Mutation in parathyroid calcium sensor

– Higher setpoint

• Low urinary calcium/creatinine <0.01

• No end organ damage

• No treatment required

Malignancy associated hypercalcemia

• Most common cause of hypercalcaemia in hospitalized patients

• Humoral hypercalcaemia (paraneoplastic)

– Tumor cells may secrete:

• PTH, PTHrP

• 1,25(OH)D3

• RANKL

– Epithelial cc (lung, cervix); bladder cancer; ovarial cancer; lymphomas; multiple

myeloma

• Local osteolytic hypercalcaemia

– Direct osteolytic effetc of tumor metastases in the bones

• PTHrP (PTH-related Protein)

– structure similar to PTH, same receptor, autocrine/paracrine effects

– not synthesized in parathyroids, no role in endocrine regulation of Ca-P

– Physiological importance: fetal and neonatal bone development

– Produced in uterus and placenta of pregnants, and in lactating breast

– Pathology: secreted by bronchial-, breast-, kidney-, bladder-, esophageal

cc. cells

Granulomatous disease

• Sarcoidosis, Tuberculosis, Leprosy

• Activation of 1 alpha hydroxylase (macrophage)

– conversion 25-OH Vitamin D increased level of 1,25(OH)

Vitamin D

• PTH low

• Treatment: glucocorticoids

Secondary hyperparathyroidism

Chronic hypocalcemia secondary hyperparathyroidism

• Chronic renal failure (most important)

• Dietary deficiency of vitamin D or calcium

• Decreased intestinal absorption of vitamin D

• Drugs that cause rickets or osteomalacia (phenytoin,

phenobarbital etc.)

• Excessive intake of inorganic phosphate compound

• Pseudohypoparathyroidism

• Severe hypomagnesemia

Milk-alkali syndrome (Burnett’s syndrome)

• Hypercalcemia from excess ingestion alkali

and calcium

– Excessive Milk or calcium supplements

– Excessive soluble alkali (absorbable antacid)

– Sodium bicarbonate, calcium carbonate

– Potentiated by Vitamin D supplementation

• Chronic milk-alkali leads to renal

insufficiency

– Soft tissue calcification of kidneys

– Nephrocalcinosis

Milk-alkali syndrome (Burnett’s syndrome)

Usually peptic ulcer, or

similar complaints

P homeostasis

Etiologies of Hyperphosphatemia

• Increased GI intake – Fleet’s phospho-soda

• Decreased urinary excretion – Renal failure

– Low PTH (hypoparatyrodism)

• after thyroidectomy, after I131 treatment, autoimmune

• Cell lysis – Rabdomyolysis

– Tumor lysis syndrome

Etiologies of Hypophosphatemia

• Decreased GI Absorption

– Decreased dietary intake (rare in isolation)

– Diarrhea / Malabsorption

– Phosphate binders (calcium acetate, Al & Mg containing antacids)

• Decreased bone resorption / Increased bone

mineralization

– Vitamin D deficiency / low calcitriol

– Hungry bones syndrome

– Osteoblastic metastases

• Increased urinary excretion

– Elevated PTH (as in primary hyperparathyroidism)

– Vitamin D deficiency / low calcitriol

– Fanconi syndrome

• Internal redistribution

FGF-23 and its role in the phosphate

homeostasis

• Fibroblast growth factor-23

• Produced mainly by bone and connective tissue

• Effects

– In the kidney

• inhibits tubular P reuptake – phosphaturia

• inhibits 1α-hydroxilase activity

– Induces 24-hydroxilase activity (calcitriol ↓)

• FGF23 mRNA expression is stimulated by:

– calcitriol

– hyperphosphataemia (indirect effect)

Regulation of FGF-23

FGF23 induced disorders of

phosphate metabolism

• Common: FGF23↑

• Symptoms:

– hypophosphataemia, low calcitriol level, BMD↓ (bone density)

• Genetic diseases:

– X-linked hypophosphataemia (XLH)

• Mutation of PHEX gene, inactive PHEX protein /1:20000/)

– (PHEX: „phosphate-regulating gene with homologies to endopeptidases on

the X-chromosome”)

• Function of PHEX: inactivates FGF23 (indirect effect)

– Autosom. dom. hypophosphataemic ricketts (ADHR)

• rare; mutant FGF23, resists proteolysis: high circulating FGF23 levels

• Tumor induced osteomalacia (TIO)

– Mainly benign mesenchymal tumors produce FGF23

Metabolic bone diseases

Normal

Matrix

Minerals

Osteoporosis Osteomalacia Combined

Model of risk factors

Osteoporosis

A systemic skeletal disease characterized by low bone mass and

microarchitectural deterioration of bone tissue, with a consequent

increase in bone fragility and susceptibility to fracture.

• Chronic pain

• Height loss

• Kyphosis

• Decreased self-esteem

• Restrictive lung dx

• Constipation, abdominal pain

• Depression

Trabecular structure in osteoporosis

Importance of osteoporosis

Risk factors for osteoporotic fractures:

• Hypogonadism in men

• Alcoholism

• Current cigarette smoking

• Low calcium intake (lifelong)

• Inadequate physical activity

• Dementia

• Recurrent Falls

• Poor health/frailty

• Personal history of fracture as an adult

• History of fracture in a first degree relative

• Caucasian

• Female

• Low body weight (<55 kg)

Estrogen deficiency

Early menopause (<age 45)

Bilateral oopherectomy

Prolonged amenorrhea (>1 yr)

Classification of ostoporosis

Primary

• Postmenopausal

– Decreased estrogen results in increased osteoclastic activity

without increased osteoblastic activity

– Bone loss – 2-3% per year of total bone mass

– Most common fx: vertebral, distal forearm

• Age related – 3rd decade of life starts slow decline in

bone mass at rate of 0.5-1% per year

– Most common types of fx: hip and radius

– F>M

Secondary

Risk factors of osteoporosis

Pathogenesis of Type I osteoporosis

Pathogenesis of Type II osteoporosis

Osteomalatia

Vitamin D – the dentists point of view

• D – vitamin overdose »Hypoplastic enamel

(if during tooth development )

• D – vitamin deficinecy - Dentin: dentinmatrix problems

(irregular dentin-predentin interface)

- Enamel: thin, decreased mineralization, irregular surface;